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Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
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16
Zinc

The trace element zinc is essential to at least 80 different enzymes in the human central nervous system (CNS), including DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) polymerases, metalloproteinases, and many dehydrogenases in intermediary metabolism, such as lactate dehydrogenase and pyruvate carboxylase (Tapiero and Tew, 2003). Zinc also is a structural component of a family of DNA-binding transcription factors known as zinc-finger proteins that are essential for gene expression (Klug and Schwabe, 1995; O’Halloran, 1993). Nuclear receptors, such as those that mediate the transcriptional roles of thyroid hormones, glucocorticoids, retinoic acid, vitamin D, and estrogen, are all zinc-finger proteins (Freedman and Luisi, 1993), and function as key players in the CNS.

ZINC AND THE BRAIN

In addition to the zinc that is bound to enzymes, transcription factors, and other proteins, about 10 percent of CNS zinc is in the free form and is associated with presynaptic vesicles of glutamatergic neurons. Although neurons containing free zinc are found in many regions of the brain, including the cortex, amygdala, and olfactory bulb, the neurons of the hippocampus have the highest concentrations of free zinc. The zinc in these vesicles is released into the synaptic cleft, where it modulates the activity of a variety of postsynaptic receptors including N-methyl-D-aspartate (NMDA) receptors, gamma-aminobutyric acid (GABA) receptors, and voltage-gated calcium channels (Matias et al., 2006; Stoll et al., 2007). Regulation of NMDA receptor subunit expression also has been shown to be regulated by zinc (Levenson, 2006).

In addition to the important neuromodulatory roles of free zinc, it has been repeatedly shown that excessive release of zinc from synaptic boutons can result in postsynaptic neuronal death. Neurons in brain regions with high concentrations of free zinc, such as the hippocampus, are thus particularly vulnerable to zinc-mediated damage and death. Additionally, after CNS injury, large quantities of free zinc can be released, not only from presynaptic vesicles but also from metalloproteins and from mitochondrial zinc pools, result-

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

ing in neuronal damage and death in a variety of brain regions (Frederickson et al., 2004; Sensi and Jeng, 2004).

Traumatic brain injury (TBI) induces a variety of damaging oxidative processes, and a number of studies show a role for zinc deficiency in the induction of reactive oxygen species (ROS). Zinc deficiency may therefore exacerbate the oxidative damage associated with TBI. This hypothesis is supported by work in cultured rat neurons (differentiated PC12 cells) showing that deficiencies in extracellular zinc resulted in an increase in neuronal oxidation via the activation of the NMDA receptor. This in turn led to calcium influx and to the calcium-mediated activation of protein kinase C/NADPH (nicotinamide adenine dinucleotide phosphate) oxidase as well as nitric oxide synthase (Aimo et al., 2010). Other work has implicated zinc deficiency in mitochondrial accumulation and release of ROS (Corniola et al., 2008). This mechanism is dependent on the tumor suppressor protein p53. Nuclear targets of p53 in zinc deficiency include genes that arrest the cell cycle and induce apoptotic mechanisms leading to cell death (Corniola et al., 2008). Finally, in response to TBI, anti-oxidant mechanisms are increased in the brain. For example, increases in several isoforms (I, II, and III) of the zinc- and copper-binding protein metallothionein have been reported after brain injury (Penkowa et al., 2001; Yeiser et al., 1999). Zinc deficiency blunts this response. Because the metal-binding metallothioneins have been shown to play an antioxidant role, these data suggest that zinc deficiency may impair antioxidant mechanisms that are needed to protect neurons and other cell types in the brain after TBI.

A relevant selection of human and animal studies (from the year 1990) examining the effectiveness of zinc supplementation on providing resilience or treating TBI in the acute and subacute phases of injury is presented in Table 16-1. This table also includes some supporting evidence from human studies on zinc supplementation for other CNS injuries, such as stroke and seizure. The occurrence or absence of adverse effects in humans is included if reported by the authors.

USES AND SAFETY

Dietary requirements for zinc are determined not only by the roles of zinc in the brain, but also by the necessity of adequate zinc for immune function, tissue repair and replacement, nutrient digestion, and energy metabolism in all organ systems. There is, however, no single widely accepted or routinely available biomarker for zinc status (IOM, 2006). Marginal zinc deficiency is particularly difficult to identify and is thus likely to go unrecognized. The Committee on Mineral Requirements for Cognitive and Physical Performance of Military Personnel (IOM, 2006) reported that high-intensity exercise can increase urinary zinc excretion by 20–40 percent. This, combined with severe environmental conditions that promote sweating, means that many active-duty military personnel have high zinc losses. These losses must be replaced by dietary intake.

The current Recommended Dietary Allowance (RDA) for zinc in the general population is 9 mg/day for females between the ages of 14 and 18, 8 mg/day for females 19 years and older, and 11 mg/day for males 14 years and older. In the general population, data from the National Health and Nutrition Examination Survey (2002) suggest that 11 percent of males and 17 percent of females have regular intakes below the recommended amounts. Owing to the increased requirements resulting from physical activity and potential increased excretion (via sweat and urine, as well as increased muscle turnover), the Military Daily Recommended Intake (MDRI) for zinc is 12 mg/day for females and 15 mg/day for males (IOM, 2006). Revisions to the MDRIs, based on current DRIs, are imminent.

Because of zinc’s important role in the modulation of immunity, zinc supplements have

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

TABLE 16-1 Relevant Data Identified for Zinc

Reference

Type of Injury/Insult

Type of Study and Subjects

Treatment

Findings/Results

Tier 1: Clinical trials

Aquilani et al., 2009

Subacute stroke patients with low Zn2+ intake (< 6.6 mg/day)

Randomized, prospective, placebo-controlled, double-blind trial

Postinjury, Zn2+ supplementation at 10 mg/day or placebo

Compared to baseline values, all patients had significantly greater daily carbohydrate (p=0.03) and zinc intake (p < 0.001) and lower National Institute of Health Stroke Scale (NIHSS) scores (p < 0.001) at 30 days.

na=26

Compared to patients assigned to placebo, patients assigned to zinc supplementation had greater body weight (p=0.002), daily energy intake (p=0.02), protein intake (p=0.04), lipid intake (p=0.01), and zinc level (p < 0.001) at 30 days.

Zinc-treated patients also had higher level of serum albumin (p=0.001) and greater improvement in NIHSS score (p=0.04) than controls. And zinc intake was inversely correlated to NIHSS score (rb=−0.46, p< 0.02).

No adverse effects of zinc were mentioned.

Young et al., 1996

Severe TBI

Randomized, prospective, double-blind, placebo-controlled trial

Postinjury, elemental zinc at standard level of 2.5 mg or supplementation at 12 mg for 15 days, then tablets of 22 mg elemental zinc or placebo for 3 months

Although there was no difference between the standard (2.5 mg) group and the supplemented (12 mg) group on serum zinc level, the supplemented group had significantly higher levels of zinc in urine at days 2 (p=0.0001) and 10 (p=0.01). But the significance disappeared at week 3.

n=68 TBI patients

Supplemented group also had higher mean serum pre-albumin level (p=0.003) and mean retinol-binding protein levels (p=0.01) at 3 weeks.

After adjusting for baseline value, supplemented group had higher mean Glasgow Coma Scale (GCS) score at day 28 (p=0.03) and mean motor GCS score at days 15 (p=0.005) and 21 (p=0.02), although there was no statistically significant difference in the raw GCS scores.

No adverse effects were mentioned.

Tier 2: Observational studies

None found

 

 

 

 

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

Reference

Type of Injury/Insult

Type of Study and Subjects

Treatment

Findings/Results

Tier 3: Animal studies

Hellmich et al., 2008

TBI

Adult, male Sprague-Dawley rats

Calcium ethylenediaminetetraacetic acid (EDTA)

Compared to saline-treated rats, rats pretreated with CaEDTA had significantly fewer Flouro-Jade (FJ, showing injured cells) stained cells in CA1 (p < 0.05) and rats treated with CaEDTA after TBI had reduced FJ-stained cells in CA3 (p < 0.02).

Although both pre- and postinjury administration of CaEDTA increased the expression of antiapoptotic gene Bcl-2, only pretreatment was significant when compared to saline-treated rats (p < 0.05). And only postinjury treatment with CaEDTA increased the expression of Bax (p < 0.05 vs. saline-treated and pretreated rats) and caspase 3 genes (p < 0.05 vs. saline-treated rats only).

CaEDTA treatment had no significant effect on spatial memory. And injured rats with and without CaEDTA treatment and treated, sham-injured rats all had significantly worse performance on the Morris water maze test (p < 0.05) compared to untreated, sham-injured rats.

Hellmich et al., 2007

TBI, fluid percussion injury (FPI)

Adult, male Sprague-Dawley rats

Lamotrigine or nicardipine

At 4 hours post-TBI, injured rats had significant increase in number of neurons with Flouro-Jade (FJ, showing injured cells) and Newport Green (NG, showing zinc positive cells) staining in CA1, CA3, and dentate gyrus regions of the hippocampus (p < 0.05). At 24 hours after injury, increased number of FJ- and NG-positive cells was seen in the CA1 and CA2 regions (p < 0.05), with stained cells seen in rats with severe injury. In the dentate gyrus, increase in stained cells was seen only in moderately injured rats (p < 0.05).

Both lamotrigine and nicardipine led to a decrease on FJ- and NG-stained neurons in CA1 (p < 0.05), and lamotrigine led to decrease of stained cells in CA3 (p < 0.05).

There was no significant difference in the expression of Bcl-2, caspase 3 and caspase 9, and Hsp 70 between the two staining methods. However, within-rat variability was smaller for FJ staining than NG.

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

Reference

Type of Injury/Insult

Type of Study and Subjects

Treatment

Findings/Results

Hellmich et al., 2004

TBI, FPI

Male Sprague-Dawley rats

Preinjury, calcium EDTA (100mM) 30 minutes before injury or no treatment

Treatment with EDTA was significantly associated with increased expression of neuroprotective genes and antioxidant enzymes.

EDTA also significantly increased expression of cell cycle regulatory genes and reduced apoptotic cell death after TBI up to 85%. Results were consistent with microarray studies describing changes in the expression of genes in several signaling and cellular pathways after TBI.

Yeiser et al., 2002

TBI, unilateral cortical stab wounds

Adult, male Sprague-Dawley rats

Postinjury, zinc diets (standard: 30 mg/kg; moderately deficient: 5 mg/kg; and supplemental: 180 mg/kg)

Compared to rats fed with standard amount of zinc (controls), serum zinc level was significantly lower in zinc-deficient rats (p ≤ 0.05) and was not significantly different in zinc-supplemented rats. There was no significant between-group difference regarding zinc levels in the brain.

Compared to controls, deficient rats had greater number of cells stained with terminal deoxynucleotidyl transferase dUTP nick end labeling (p ≤ 0.05).

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

Reference

Type of Injury/Insult

Type of Study and Subjects

Treatment

Findings/Results

Penkowa et al., 2001

TBI

Adult, male Sprague-Dawley rats

Preinjury, normal diet (43.3 mg Zn/kg, 6.5 mg Cu/kg), zinc-deficient diet (1.9 mg Zn/kg), copper-deficient diet (0.8 mg Cu/kg), or zinc pair-fed diet (43.3 mg Zn/kg)

Compared to uninjured controls, zinc-deficient rats had lower food consumption, lower level of brain zinc, and decreased weight gain (p < 0.05 for all three). Zinc-deficient rats had decreased weight gain compared to pairfed rats, too (p < 0.05).

Injured, zinc-deficient rats had greater number of round hypertrophic microphages at the periphery of the lesion and in the parenchyma than injured, normally fed rats (p < 0.05) and uninjured controls (p < 0.001). Both injured and uninjured zinc-deficient rats had decreased astrogliosis around the lesion and long thin processes than corresponding normally fed rats (p < 0.05 for both).

Injured zinc-deficient rats had more apoptotic cells (neurons, astrocytes, and microglia/microphages) than uninjured controls (p < 0.001) and injured normally fed rats (p < 0.05). Expression of metallothionein (MT) isoforms I and II in injured, zinc-deficient rats was greater compared to uninjured controls (p < 0.001), but lower compared to injured, normally fed rats (p < 0.05). Expression of MT-III was higher in injured, zinc-deficient rats compared to both controls (p < 0.001) and injured, normally fed rats (p < 0.05).

Analysis of oxidative stress markers showed that injured, zinc-deficient rats had increased levels of MDA (malondialdehyde), NITT (protein tyrosine nitration), and NF-κB (nuclear factor kappa B) compared to both uninjured controls (p < 0.001 for all three markers) and injured, normally fed rats (p < 0.05 for all three).

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

Reference

Type of Injury/Insult

Type of Study and Subjects

Treatment

Findings/Results

Suh et al., 2000

Moderate and severe TBI, induced by weight drop model

Male Sprague-Dawley rat

Postinjury, calcium EDTA (for ion zinc chelation), zinc-EDTA (prevents zinc chelation), or saline

Vesicular zinc was loss from boutons in impacted area within 6 hours of injury.

In rats that underwent severe trauma, neurons stained with N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) can be seen 1 hour after TBI, especially in the hilar and infragranular regions in dentate gyrus. TSQ-labeled neurons can be seen in the cortex and thalamic regions after 24 hours. The main difference between severe and moderate trauma was there was more florescent neurons in the dentate granule layer and subgranular hilar regions.

Results from TSQ florescence were confirmed by eosin staining showing neuron degeneration.

Administration of calcium EDTA reduced the number of eosinophilic neurons in the dentate gyrus, hilus, and CA1 regions (p < 0.05 vs. saline for all three). The number of eisonophilic neurons was not affected by zinc-EDTA.

a n: sample size.

b r: correlation coefficient.

been used in a variety of settings to improve immune function and reduce inflammation (see Prasad, 2009; Scrimgeour and Condlin, 2009 for recent reviews). A 2008 meta-analysis of the four available randomized trials of zinc supplementation and clinical outcomes in critically ill patients showed only small, statistically insignificant improvements in mortality and length of stay in intensive care (Heyland et al., 2008). However, zinc supplementation appears to be associated with improvements in markers of immune function in a variety of other noncritically ill patients. For example, a 2010 report showed that 18 months of daily zinc supplementation (12 mg for women and 15 mg for men) significantly reduced the likelihood of immunological failure, rate of diarrhea, and mortality in HIV-infected adults (Baum et al., 2010). The use of zinc to treat cold and flu symptoms also has become very popular, albeit with conflicting scientific evidence on efficacy. Although some studies have reported no improvements in cold symptoms (Eby and Halcomb, 2006), a meta-analysis of double-blind, randomized, controlled trials suggested that zinc gluconate may be effective in reducing the symptoms and duration of the common cold in healthy people when administered within 24 hours of onset of symptoms (Singh and Das, 2011). To produce these effects, however, the daily dose varied between 30 mg zinc in syrup preparation and 80–190 mg zinc in lozenge form (Singh and Das, 2011).

This raises the issue of zinc overload. Currently, the Tolerable Upper Intake Level (UL) for zinc is set at 40 mg/day; the minimum effective dose discussed for treatment of colds

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
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would significantly exceed this amount. A number of recent reports have shown that prolonged excessive zinc overload from misuse of dental preparations results in potentially fatal copper deficiency, characterized by pancytopenia and myelopolyneuropathy (Afrin, 2010; Hedera et al., 2009). These data suggest that recommendations to supplement zinc for any reason, including for the treatment of TBI, should include cautionary advice not to chronically exceed the UL for zinc intake.

EVIDENCE INDICATING EFFECT ON RESILIENCE

Human Studies

As with other nutrients or food components, the committee found no human studies that have examined the potential benefits of zinc in TBI or in other related diseases or conditions included in the review of the literature (subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy).

Animal Studies

Given the evidence, both clinical and experimental, showing a possible role for the use of zinc as a treatment in TBI, a 2010 study (Cope et al., unpublished) sought to test the hypothesis that zinc supplementation prior to injury could increase resilience and improve outcomes of brain injury. The effect of diet was assessed using the controlled cortical injury model of TBI in adult rats. This model of severe injury induced anhedonia, a depression-like symptom, in the rat, as measured by the two-bottle saccharin preference test. Although this symptom was observed in injured animals that were fed a diet with adequate zinc (30 ppm), four weeks of zinc supplementation (180 ppm) prior to the injury prevented the appearance of anhedonia following TBI.

Animals also were monitored for the appearance of anxiety-like behaviors. Four weeks of a diet with marginal zinc deficiency (5 ppm) resulted in anxiety, as measured by the elevated plus maze, even in the absence of brain injury. The development of anxiety has been previously reported in zinc-deficient rats (Takeda et al., 2008; Tassabehji et al., 2008) and reviewed in 2010 (Cope and Levenson). The earlier reports used diets that were more severely limited in zinc (< 3 ppm), used weanling animals that are highly susceptible to zinc deficiency, or both. The most recent work is the first report to show that even diets marginally deficient in zinc may result in anxiety. Cortical injury produced additional evidence of anxiety; however, animals fed the zinc-supplemented diet prior to injury appeared to have greater resilience to the effects of injury on anxiety. Not only did supplementation partially prevent anxiety-like behaviors, supplemented animals also showed prevention of significant increases in adrenal weight measured two weeks after TBI (Cope et al., unpublished).

Because loss of cognitive function can be one of the most debilitating deficits associated with TBI, the 2010 study also examined whether zinc supplementation could prevent losses in spatial learning and memory. While controlled cortical impact resulted in significant performance deficits on the Morris water maze test in animals fed a diet adequate in zinc, rats that were fed the zinc-supplemented diet (180 ppm) prior to TBI showed no differences from sham-operated control rats at any point during the 10-day cognitive trial, suggesting that zinc supplementation may improve cognitive resilience in the event of brain injury (Cope et al., unpublished). Future work will be needed to determine the possible uses of zinc supplementation to improve resilience across the range of traumatic brain injuries, including mild TBI.

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
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EVIDENCE INDICATING EFFECT ON TREATMENT

Human Studies

Traumatic brain injury results in significantly depressed serum zinc levels as well as increased urinary zinc excretion. A 1986 report showed that urinary zinc excretion was proportional to the severity of the brain injury (McClain et al., 1986). The most severely injured patients in this study had mean urinary zinc levels that were 14 times normal values, suggesting rapid zinc depletion. Additionally, patients with severe head injuries develop hypoalbuminemia (most likely secondary to increased interleukin-1-mediated transendothelial movement of albumin), as well as evidence of inflammation, including increases in acute-phase proteins (e.g., C-reactive protein, ceruloplasmin), and elevated white blood cell counts (McClain et al., 1988; Young et al., 1988). The impact of these factors on zinc availability and zinc metabolism is potentially significant. Because albumin is the major serum transport protein for zinc, hypoalbuminemia would potentially impair both zinc transport and availability. Induction of cytokines such as interleukin-1 may further compromise zinc availability and reduce zinc stores that are already significantly depleted by increased urinary excretion.

Given the apparent role of TBI in compromising zinc status, Young et al. (1996) sought to test the effectiveness of using zinc supplementation after TBI to reduce zinc losses, maintain protein balance, and improve neurological outcomes. Within 72 hours of injury, 68 patients with severe closed head injuries were randomly assigned to either an adequate zinc (2.5 mg/day) or supplemental zinc (12 mg/day) treatment group. These zinc levels were administered intravenously as zinc sulfate in conjunction with total parenteral nutrition. Supplements were administered in a double-blind fashion for the initial 15 days and followed by 22 mg intravenous zinc (as zinc gluconate) or placebo for the remainder of the study. Zinc supplementation resulted in increased levels of serum pre-albumin and retinol-binding protein, suggesting improved protein synthesis and a role for supplemental zinc in maintaining visceral protein in TBI patients. Two weeks after injury, patients in the zinc-supplemented group had better Glasgow Coma Scale scores than control patients given adequate zinc. These improvements were maintained at 21 and 28 days. Interestingly, the differences between the groups were seen despite the fact that neither serum zinc concentrations nor zinc levels in cerebral spinal fluid were changed by zinc supplementation, suggesting that the zinc is taken up into tissues after administration, and illustrating the fact that serum zinc levels are not a good indicator of zinc status. One month after TBI, mortality in the control group receiving adequate zinc was 26 percent, compared to 12 percent in the group receiving supplemental zinc. Caution should be exercised, however, when interpreting the mortality data, because a larger number of patients in the control group (13 vs. 6 in the zinc-supplemented group) required craniotomies for hematoma evacuation during the course of the study.

The efficacy of treatment with zinc also has been tested after ischemic injury. A small (26 patients assigned to receive either zinc supplementation or placebo) human study sought to explore the effectiveness of replacing zinc in stroke patients who had dietary zinc intakes that were lower than two-thirds of the RDA. In these patients, zinc replacement (10 mg/day) improved outcomes measured by the National Institutes of Health Stroke Scale 30 days after stroke (Aquilani et al., 2009). Although this work does not address the effect of zinc supplementation using levels that are higher than the RDA as a treatment for neuronal injury, it does suggest that, at the very least, maintaining adequate zinc levels after injury is important for recovery.

Finally, as many as 40 percent of patients hospitalized with TBI develop major depres-

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

sion, making it the most common long-term complication of TBI (Jorge and Starkstein, 2005). Although there are no data on the use of supplemental zinc to improve antidepressant drug treatment in patients with TBI-associated depression and although this report does not further review long-term health disorders associated with TBI, the use of zinc to improve mood may be effective among this patient population.

Animal Studies
Zinc Deficiency

Because military personnel may be at risk for developing zinc deficiency, and TBI further increases zinc losses, it is important to understand the possible effects of zinc deficiency on the cellular and molecular mechanisms associated with TBI. Animal models not only permit the study of these mechanisms in a controlled fashion, but also have provided useful information about the role of zinc in TBI. For example, an examination of DNA damage after infliction of a unilateral cortical stab wound in adult rats found that zinc deficiency (induced with a moderately deficient diet that did not result in anorexia) led to a significant increase in terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL)-positive cells at the site of injury compared to animals with adequate zinc. TUNEL staining, a marker of DNA fragmentation and cell death, in combination with nuclear morphology and cell-specific markers, revealed that moderate zinc deficiency caused both apoptosis and necrosis of macrophages and ameboid microglia involved in the clearance of debris following TBI (Yeiser et al., 2002). More severely zinc-deficient diets that induced anorexia resulted in increased neuronal death and significant increases in gliosis at the site of injury (Penkowa et al., 2001). These data combine to suggest that zinc deficiency not only increases the severity of damage after TBI, but also may prevent debris clearance and inhibit repair at the site of the injury.

Zinc Toxicity

Animal models also have been used to show that TBI can result in the accumulation of free zinc that leads to neuronal death (Hellmich et al., 2004; Yeiser et al., 1999). In addition to affecting the site of injury, TBI produced either by fluid percussion injury (Hellmich et al., 2004) or mechanical cortical trauma (Suh et al., 2000) resulted in neuronal death in the dentate gyrus, hilus, and CA1 regions of the hippocampus. Not only does the neuronal death appear to be associated with presynaptic zinc release (Hellmich et al., 2007), but also the cell death was largely prevented by treatment with the zinc chelator calcium disodium ethylenediamine tetraacetate (Hellmich et al., 2004, 2008), suggesting that zinc in high concentrations after TBI is neurotoxic. Despite histological evidence of neuronal survival, however, chelation of zinc after TBI did not improve the spatial memory deficits associated with brain injury (Hellmich et al., 2008).

This understanding of the possible role of free zinc in neuronal death raises the question of whether clinicians should be treating brain-injured patients with supplemental zinc, particularly in acute periods after severe injury when the blood-brain barrier that regulates brain zinc uptake has been disrupted. An animal model of TBI showed that four weeks of dietary zinc supplementation (180 ppm) after TBI did not significantly increase cell death (as measured by TUNEL labeling) in any cell type examined, including microglia, macrophages, neurons, or oligodendrocytes at the site of injury or any other region of the CNS (Yeiser et al., 2002). These data suggest that concerns about the potential neurotoxicity of

Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

enteral zinc supplementation in TBI patients are unwarranted. Reports that intraperitoneal injections of zinc significantly increased the infarct size and impaired motor behavior after focal ischemia in subject rats suggest, however, that caution is warranted when using zinc parenterally in moderately to severely injured patients (Levenson, 2005; Shabanzadeh et al., 2004).

CONCLUSIONS AND RECOMMENDATIONS

Although the available evidence suggests that zinc may be an effective treatment for TBI, there are many unanswered questions that prevent its optimal use in the clinical setting. Future research will be needed to determine the best practices for zinc administration after TBI and to populations at risk of TBI. The safety of zinc supplementation, especially in patients with moderate to severe TBI, also must be evaluated.

In the acute care situation, the available clinical evidence suggests that after TBI, zinc deficiency should be prevented to maintain visceral protein and optimize the potential for neurological recovery. The only acute dose of supplemental zinc that has been tested in a clinical setting is 12 mg/day administered intravenously for the first 15 days after injury. After day 15, an oral dose of 22 mg/day was used. With the UL set at 40 mg/day, these doses are not likely to have adverse effects. However, the impact of parenteral administration of zinc has not been independently investigated, nor has it been compared to enteral feeding in a TBI model. Doses of up to 30 mg/day have been provided to critically ill patients without obvious adverse clinical impacts.

Although there have been no studies to determine the possible efficacy of zinc supplementation in TBI patients who are being treated for depression and depression-related disorders, the available clinical evidence suggests that this approach may be warranted.

RECOMMENDATION 16-1. Based on a report showing efficacy in humans, the committee recommends that animal studies be conducted to determine the best practices for zinc administration after concussion/mild, moderate, and severe TBI, such as determining the therapeutic window for zinc administration, the length of treatment time for greatest efficacy, and the optimal level of zinc to improve outcomes. These trials should also evaluate the safety of zinc, based on concerns about toxicity and overload. Results from these studies should be used to design human clinical trials using zinc as a treatment for TBI.


RECOMMENDATION 16-2. Future work is needed in both humans and animal models to determine the extent to which chronic preinjury zinc supplementation can improve resilience in the event of a TBI.

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Aimo, L., G. N. Cherr, and P. I. Oteiza. 2010. Low extracellular zinc increases neuronal oxidant production through NADPH oxidase and nitric oxide synthase activation. Free Radical Biology and Medicine 48(12):1577–1587.

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Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
×

Cope, E. C., and C. W. Levenson. 2010. Role of zinc in the development and treatment of mood disorders. Current Opinion in Clinical Nutrition and Metabolic Care 13(6):685–689.

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×

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Suggested Citation:"16 Zinc." Institute of Medicine. 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington, DC: The National Academies Press. doi: 10.17226/13121.
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Traumatic brain injury (TBI) accounts for up to one-third of combat-related injuries in Iraq and Afghanistan, according to some estimates. TBI is also a major problem among civilians, especially those who engage in certain sports. At the request of the Department of Defense, the IOM examined the potential role of nutrition in the treatment of and resilience against TBI.

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